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Many epidemiological studies have pointed to a link between obesity and a higher risk of Alzheimer’s disease. Now, scientists led by Paresh Dandona at the State University of New York, Buffalo, report that people who undergo gastric bypass surgery to lose weight have lower levels of several AD-related proteins in their blood six months later. The finding, presented 5 June 2011 at The Endocrine Society’s 93rd annual meeting in Boston, Massachusetts (see press release), implies that behavioral changes could alter AD risk, although this is far from proven.

Dandona and colleagues performed the surgery on 15 morbidly obese people with type 2 diabetes, who lost an average of 86 pounds each. When the researchers compared blood samples taken before surgery with samples taken six months later, they saw, as expected, that the patients’ insulin resistance index had fallen dramatically, a sign that their diabetes had improved. Also expected was that levels of numerous inflammatory markers, such as endotoxins, Toll-like receptors 2 and 4, NF-κB, C-reactive protein, and IL-6, dropped by an average of 25 to 35 percent, Dandona told ARF. Inflammation has been tied to numerous neurodegenerative diseases (see, e.g., ARF related news story).

“What was really novel and exciting was that the expression of genes related to AD fell,” Dandona said. “For the first time, there is a relationship between dramatic weight loss and reduction of [expression of] Alzheimer’s genes.” The level of APP protein in white blood cells dropped by about one-quarter, and presenilin-2 and glycogen synthase kinase-3β declined by similar amounts. Presenilin-2 is part of the γ-secretase enzyme that releases the Aβ peptide from APP, while the kinase has been implicated in toxicity of tau, the protein that makes neurofibrillary tangles in the AD brain. Levels in blood were used as a surrogate for what might be happening in brain, leaving open the question of whether brain chemistry is also changing. It is unclear if moderate weight loss would have the same effect. Dandona told ARF they previously looked at lower levels of weight loss, but did not see statistically significant changes in AD proteins.

Dandona is particularly intrigued by the connection between weight loss and AD genes because researchers led by John Gunstad at Kent State University, Ohio, found that people who undergo gastric bypass surgery perform better on memory tests three months later (see Gunstad et al., 2010). “If we can put the two things together, we could say that maybe bariatric surgery in the morbidly obese patient may delay or prevent the onset of AD,” Dandona speculated. To this end, Dandona is currently applying for funding to repeat his bariatric surgery study, adding cognitive tests and neuroimaging to the outcome measures. In addition, he will explore whether dramatic weight loss without surgery can lead to similar reductions in AD-related gene expression.

“I was quite excited and surprised by what they found,” said Paul Thompson at the University of California, Los Angeles. Thompson studies the relationship between obesity and AD. “The question has always been whether we can alter our genetic destiny,” Thompson said, adding that this study suggests that, under some circumstances, people can. In addition, Thompson noted that testing blood for changes in the expression of APP, PS2, and GSK-3β could be useful for epidemiologists as a relatively cheap and easy surrogate marker to see if interventions are having an effect on AD genes.

Dandona told ARF he is also pursuing the link between diabetes and AD. Type 2 diabetes, like obesity, more than doubles Alzheimer’s risk. In work published in the June Journal of Clinical Endocrinology and Metabolism, Dandona and colleagues showed that insulin infusion likewise lowers the levels of APP, PS2, and GSK-3β in the blood. The anti-diabetic drug exenatide, trade name Byetta, has the same effect, Dandona told ARF. He will investigate whether taking exenatide, a glucagon-like peptide 1 (GLP-1) analog, can improve cognitive function. Another GLP-1 mimic that improves insulin signaling, liraglutide, was recently shown by researchers in Ireland to improve memory, reduce Aβ, and protect synapses in an AD model mouse (see McClean et al., 2011 and ARF related news story). Previous diabetes drugs, such as the insulin-sensitizing agent rosiglitazone, have failed in clinical trials (see ARF related news story).—Madolyn Bowman Rogers

This is a most interesting finding. One important observation after gastric bypass surgery is that the patients are almost immediately relieved from being diabetic. This is linked to increased GLP-1 release (see, e.g., Morínigo et al., 2006). It is not understood why the intestine suddenly releases a lot more GLP-1 after this surgery, but GLP-1 re-sensitizes insulin signaling.

Importantly, GLP-1 analogues also have neuroprotective properties and reduce amyloid synthesis, plaque load, and the inflammation response in animal models of AD. Nigel Greig's group from the NIH showed that the GLP-1 analogue exendin-4 has protective properties in a triple-Tg mouse model of AD (Li et al., 2010), and we showed that the GLP-1 analogue liraglutide has very clear protective properties in an APP/PS1 mouse model (McClean et al., 2011). Both drugs are already on the market as treatments for type 2 diabetes. This new study is an interesting confirmation of the idea that GLP-1 may be neuroprotective.

It is very interesting and useful to understand that there may be a link between obesity and a higher risk of Alzheimer’s disease. Alzheimer's disease (AD) itself is a neurodegenerative disease which is characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes (Bhat, 2010). It is also important to realize that, on the other hand, behavioral changes can be related to, or contribute to, the occurrence of AD.

Insight into correlated factors of AD can suggest and stimulate further research on the developmental and psychosocial issues that contribute to AD, e.g., lifestyle and social behaviors, emotion and stress, and also on potential preventive measures.

One innovative approach focuses on the relationship between post-traumatic stress disorder (PTSD) and AD. PTSD is common among veterans returning from combat or war. There is some evidence that PTSD may be associated with reduced cognitive function. However, no study has yet investigated if PTSD increases the risk of development of AD.

Kristine Yaffe at the University of California, San Francisco, and colleagues addressed this (Yaffe et al., 2009). They studied 181,093 veterans (aged 55 years and above without dementia) and 53,155 of them were diagnosed with PTSD. Mean age was 68.8 years and 97 percent were male. They followed the veterans from 2001 through 2007, tracking whether they were diagnosed with AD or dementia.

The researchers found that veterans with PTSD in the study developed new cases of dementia at a rate of 10.6 percent over the seven-year follow-up. Those without PTSD had a rate of 6.6 percent. Even after adjusting for demographics and medical and psychiatric comorbidities, people with PTSD in the study were still nearly twice as likely to develop AD or dementia compared to veterans without PTSD (HR = 1.8, 95 percent CI = 1.7-1.9). It is also interesting to find in the study that moderate alcohol consumption reduces the risk of AD.

Nevertheless, further research should be conducted to understand more about the links between anxiety, or related psychological factors, and occurrence of AD, in order to find ways to reduce the increased risk of dementia associated with these psychological morbidities.